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5. Hematopoiesis (Dr. Vishy)
01 L1 Vishy - Intro to Host Defense / Immune System COMPLETE || 24 L6 Vishy - Hematopoiesis COMPLETE || 46 Vishy - Cells and Organs of the Immune System COMPLETE || 62 Vishy - Innate Defenses COMPLETE
Terms in this set (75)
What are the main characteristics of innate immunity?
● no immunological memory
● does not improve over time
What are the components of innate immunity? What are the cells of innate defense?
1) barriers (ex. skin, mucous membranes)
2) cells of innate defense: neutrophils, monocytes, macrophages, dendritic cells, natural killer cells (
3) anti-microbial peptides and complement
What are the characteristics of adaptive immunity?
● slow onset (not pre-formed)
● highly specific
● has immunological memory
● improves over time
What are the components of adaptive immunity? Where do the cells differentiate? What do they produce?
B lymphocytes (BAIg)
o Differentiate in bone marrow
▪ Ig molecules bind to antigens (usually proteins, but also lipids and carbs) and neutralize their effects
o Differentiate in thymus
interleukin (IL) (TIC)
▪ can activate/suppress immune system
What are the characteristics of neutrophils? What type of nucleus do they have?
Polymorphonuclear leukocytes (PMN)
because they have
Live for one day
, replaced by new ones from bone marrow
o protection against
What are the characteristics of monocytes? What type of nucleus do they have? Do they have cytoplasmic granules?
o kidney-shaped nucleus
o lack cytoplasmic granules
more effective compared to neutrophils in terms of ingesting and killing intracellular pathogens
o Live for
o can leave circulation and go to tissue, where they can differentiate to
What are the characteristics of macrophages?
o differentiated forms of monocytes
o can live for several
months to years
enhanced ability to phagocytose and kill microorganisms
What are the characteristics of dendritic cells (DCs)? What are they capable of? What cell marker do they have?
o similar to macrophage, present in tissue
o phagocytosis (solids)
CD14 cell marker
on surface (CD = cluster of differentiation)
most efficient antigen-presenting cells
What are the characteristics of natural killer (NK) cells?
o only non-phagocytic cells of innate defense
o do not attack microbes
attack virus-infected body cells
o do not "eat" cells--
causes cells to burst
o down-regulation of MHC Class I on target cells induces NK cells to
lyse target cells by releasing perforin and granulysin
▪ impacted by factors such as malignancy
What are the characteristics of T lymphocytes? What do Helper T-cells produce? What do Cytotoxic T-cells secrete?
All T-Cells have CD3
, which are associated with
MHC Class II
▪ CD4+ (helper T) cells produce
s* such as ILN-gamma, IL-4-B (growth factor), IL-5-B (cell differentiation factor)
, which recognize antigenic peptides with
MHC Class I
Mnemonic - Rule of 8: CD4 x MHC II = 8 = CD8 x MHC I
Describe the process of antigen presentation.
● Protein antigens produced or secreted by microbes are
complex and of high-molecular weight.
● T cells cannot recognize protein antigens in their native state.
● The complex protein antigens should be
internalized by dendritic cells and macrophages
and within the intracellular compartment, the protein antigen is
broken into a simple antigenic peptide
● The antigenic peptide is then
conjugated with major histocompatibility class molecule (MHC)
presented on the cell surface
e* for recognition by T cells
How are phagocytosed microbes killed intracellularly by monocytes and neutrophils (4 methods)?
● generation of reactive oxygen intermediates
● generation of reactive nitrogen intermediates
● generation of
● fusion of microbe-containing phagosome with lysosome
What are three peptides/proteins that contribute to innate immunity? What are their functions?
: sequesters iron
: cationic peptides that bind to cell surface and either
kill the microorganism or inhibit growth
: produced by neutrophils and Paneth cells (stomach)
: ciliated epithelial cells in the respiratory tract
: protein that is present in the lysosomal compartment;
which is a major cell wall component in gram-positive bacteria
What are complement components? What is the role of C3B? C3A?
o ~30 proteins that circulate blood in an inactive form
o C1-C9; factors B,D,P; regulatory proteins
C3B component participates in chain reaction (activation of MAC) and in opsonization
C3A is chemotactic (attracts phagocytes)
o when complements are activated, they form the
MAC (membrane attack complex)
Generally, describe the classical pathway of complement activation.
antigen-antibody reactions result in activation of C1 followed by C4 and C2
● This complex C142 activates C3 this result in sequential activation of C5, C6, C7, C8 and C9 (MAC).
● This complex binds to the bacterial cell surface causing lysis of the bacteria.
Generally, describe the alternate pathway of complement activation.
● In alternate pathway, infections with gram negative bacteria result in the
release of LPS
S* (Factor B, D, and P (properdin).
LPS directly activates C3
3* followed by sequential activation of C5, C6, C7, C8, and C9 and lysis of bacterial cells
What is opsonization?
Phagocytes express cell surface receptors for complement and antibodies
: complement binds to cell surface of bacteria -> gets internalized via antibodies and complement receptors, respectively
Antibody opsonization is the process by which a pathogen is marked for ingestion and destruction by a phagocyte. Opsonization involves the binding of an opsonin, e.g., antibody, to an epitope on an antigen. After opsonin binds to the membrane, phagocytes are attracted to the pathogen.
How does the innate immune system distinguish self vs. non-self? What are two significant receptors?
Pattern Recognition Receptors (PRRs)
(aka Toll-Like Receptors (TLR)) allow cells of the innate immune system to recognize patterns of microorganisms
recognizes LPS (gram-negative)
recognizes peptidoglycan and lipotechoic acid (gram-positive)
What are the three steps of T cell response? What are the different classes of antibodies? How are they produced?
1) antigen recognition
3) response: antibodies of different classes
o IgM: pentamer
o IgG: travels through the placenta
o IgE: participates in allergic reactions
o Ig A: secreted in tears and colostrum
o IgD: B cell receptor
antibody classes are produced from B cells which respond to either T cell independent or T cell dependent antigens
What is the difference between an immunogen and a hapten? How can a hapten become an immunogen?
for an antigen to be an
, it has to be a
complex protein of high molecular weight
if it has low molecular weight, it will form a
, which can bind antibodies but cannot induce antibody production/immune response
Tag hapten with carrier protein to elicit immune response
Describe the basic mechanism of T-cells.
CD8 T cells (cytotoxic T cells) recognize and bind to MHC I -> closed ended structure accommodates peptides of 8-9 AA
○ use perforin and granulysin to kill virus- infected cells (very specific)
CD4 T cells (Helper T cells) recognize and bind to MHC II -> open ended structure accommodates 18-20 AA
○ inhibit intracellular bacteria and fungi
How do B cells respond to T-cell independent antigens? How do they respond to T-cell dependent antigens?
B-Cell Response to T-Cell Independent Antigens (LPS)
● non-protein antigens -> don't present with MHC molecules
B-Cell Response to T-Cell Dependent Antigens (Proteins)
● class switching -> B cells can produce different classes of antigens based on how it is activated
What is the relationship between aging and the immune system?
Perinatal development: IgG derived from mother
Infant stage: IgA derived from mother's milk
Newborns: respond well to protein antigens
Elderly: weak immune system and weak tolerance to self-antigens
What is blood? Define hematocrit.
● The only fluid tissue in the human body-composed of cells (RBC, WBC, and platelets) + plasma
● Classified as a connective tissue
● Living cells = formed elements
● Non-living matrix = plasma
t*: the percentage of RBCs out of total blood volume
What is blood plasma? What are three important plasma proteins? What do they do?
● composed ~90% of water
● includes dissolved nutrients, salts, respiratory gases, hormones, proteins, and waste products
n*: regulates osmotic pressure
s*: help to stem blood loss when a blood vessel is injured
s*: help protect body from antigens
What are formed elements?
● Erythrocytes, leukocytes, and platelets make up the formed elements
● Only WBCs are complete cells
Mature RBCs have no nuclei or organelles, and platelets are just cell fragments
● Most formed elements survive in the bloodstream for only a
● Most blood cells do not divide but are renewed by cells in bone marrow
What is hematopoiesis? What cells are required? Where are these cells found at different stages of development?
● hematopoiesis is blood cell formation from stem cells
(pluripotent stem cells or hemocytoblasts) are
first observed in yolk sac - ALL blood cells derived from these
○ pluripotent stem cells are self-renewing and can give rise to any blood cell type
of development, stem cells are seen in
liver and spleen
, stem cells are seen in
● Ratio of differentiated cells to stem cells in bone marrow is approx 10^5: 1
What is erythropoiesis? Where does it occur?
● Erythropoiesis is the process of red blood cell formation
● Erythropoiesis occurs in the
red bone marrow
w* of the:
axial skeleton and girdles
s* of the humerus and femur
● During the process of differentiation, there is a loss of the nucleus and the cytoplasmic organelles
cytoplasm becomes completely enriched with hemoglobin
● hemocytoblast -> proerythroblast...
Describe erythrocytes. What is the majority of their content? How do they generate ATP?
Biconcave discs, anucleate, essentially no organelles
● Filled with hemoglobin (Hb) , a protein that functions in gas transport
● Structural characteristics contribute to its gas transport function
● Biconcave shape that has a
huge surface area relative to volume
Discounting water content, erythrocytes are more than 97% hemoglobin
ATP is generated anaerobically
y*, so the erythrocytes do not consume the oxygen they transport
Describe the regulation and requirements for erythropoiesis. What 4 things must be in adequate supplies? What is their average lifespan? What happens to old erythrocytes?
● Circulating erythrocytes - the number remains constant and reflects a balance between RBC production and destruction
● Too few red blood cells leads to tissue hypoxia
● Too many red blood cells causes undesirable blood viscosity
● Erythropoiesis is hormonally controlled and
depends on adequate supplies of iron, amino acids, B vitamins (B12) and Erythropoietin (EPO)
● The lifespan of an erythrocyte is
● Old erythrocytes become rigid and fragile, and their hemoglobin begins to degenerate
● Dying erythrocytes are engulfed by macrophages
● Heme and globin are separated and the iron is salvaged for reuse
Describe the formation of leukocytes. What do all leukocytes originate from? What do myeloblasts become? What do monoblasts become? What do lymphoblasts become?
All leukocytes originate from hemocytoblasts
● Hemocytoblasts differentiate into myeloid stem cells and lymphoid stem cells
Myeloid stem cells
s* become myeloblasts or monoblasts
s* develop into eosinophils, neutrophils, and basophils
s* develop into monocytes
Lymphoid stem cells
s* become lymphoblasts
*develop into lymphocytes (some become plasma cells)
What are leukocytes? What is their average life span? What is the process by which they leave capillaries? What is leukocytosis?
s*: the only blood components that are complete cells (WBCs):
● considered true immune cells - contribute to both innate and adaptive immune systems
○ Are less numerous than RBCs,
only live for 1 or 2 days
○ Make up 1% of the total blood volume
○ Can leave capillaries via
○ Move through tissue spaces
● Leukocytosis - WBC count over 11,000 per cubic millimeter
○ Normal response to bacterial or viral invasion
What are granulocytes?
s*: neutrophils, eosinophils, basophils (+mast cells)
● Contain cytoplasmic granules that stain specifically (acidic, basic, or both) with Wright's stain
● Are larger and usually shorter-lived than RBCs
● Have lobed nuclei
What are neutrophils? What are they formed from? Which 3 cytokines are involved?
formed from stem cells by GM-CSF, CSF and IL-3
● Neutrophils have two types of granules that:
○ Take up both acidic and basic dyes
○ Give the cytoplasm a lilac color
Neutrophils are our body's bacteria slayers
● Neutrophils develop primary and secondary granules
What do primary granules contain? What do secondary granules contain?
Primary (azurophilic) granules contain lysozyme, a-defensins and myeloperoxidase
■ Myeloperoxidase catalyzes reaction leading to production of
(potent microbial agent) and
The secondary granules contain lactoferrin
■ limits iron availability to microorganisms
What are eosinophils? What is their role in the immune system? In allergic reactions?
● Eosinophils account for 1-3% of WBCs
● Have red-staining, bilobed nuclei connected via a broad band of nuclear material
● Have red to crimson (acidophilic) large, coarse, lysosome-like granules
● Lead the body's counterattack against
Lessen the severity of allergies by phagocytosing immune complexes
What are basophils? What is the shape of their nuclei? What is histamine?
● Account for 0-1% of WBCs and:
U- or S-shaped nuclei
i* and contain acidic granules that secrete histamine
● Are functionally similar to mast cells
● Have large, purplish-black (basophilic) granules that contain histamine
e*: inflammatory chemical that acts as a vasodilator and attracts other WBCs (antihistamines counter this effect)
● Mast cells are differentiated forms of basophils
play important role in allergic rxns by releasing histamines -> contract smooth mm which increases vascular permeability -> inflammation
What are agranulocytes?
● lack visible cytoplasmic granules
● similar structurally, but functionally distinct and unrelated
● spherical (lymphocytes) or kidney-shaped (monocytes) nuclei
What are monocytes? What is the shape of their nuclei? What is their life span?
● Monocytes account for 4-6% of leukocytes
● They are the largest leukocytes
● They have abundant pale-blue cytoplasms
● They have purple-staining,
U- or kidney-shaped nuclei
● They leave the circulation, enter tissue, and differentiate into macrophages
● Life span of
What are macrophages? What cytokine is responsible for their formation? What is their life span?
F* induced pluripotent stem cells to form monocyte
● Are highly mobile and actively phagocytic
● Activate lymphocytes to mount an immune response
● Life span of a
few months to one year
● Innate defense by controlling intracellular infections
What are lymphocytes? Which cytokine is responsible for their formation?
● Account for 25-35% or more of WBCs and
● Have large, dark-purple, circular nuclei with a thin rim of blue cytoplasm
● Are found mostly enmeshed in lymphoid tissue (some circulate in the blood)
● There are two types of lymphocytes: T cells and B cells (participate in adaptive immunity)
s* undergo differentiation in bone marrow where they acquire B cell receptor or IgD
s* give rise to plasma cells, which produce antibodies
s* migrate to thymus to differentiate to T lymphocytes
s* produce cytokines that activate the immune system
7* induces lymphocyte formation from pluripotent stem cells
What is leukopoiesis? What two things is it hormonally stimulated by? What are two important sources?
● Leukopoiesis is hormonally stimulated by two families of cytokines (hematopoietic factors) -
interleukins and colony-stimulating factors (CSFs)
● Interleukins are numbered (e.g., IL-1, IL-2), whereas CSFs are named for the WBCs they stimulate (e.g., granulocyte-CSF stimulates granulocytes)
Macrophages and T cells are the most important sources of cytokines
● Many hematopoietic hormones are used clinically to stimulate bone marrow
Describe the development of RBCs, granulocytes and agranulocytes from stem cells
What is apoptosis?
● Apoptotic cells undergo changes in morphology (ex. shrinkage, membrane blebbing, condensation of chromatin, DNA fragmentation)
● cells get broken to small
s* without release of intracellular enzymes or cytoplasmic molecules to surrounding
● apoptotic bodies are phagocytosed and cleared by macrophages
What are initiators of apoptosis? Promoters? Inhibitors?
● Initiator: Fas, p53
● Promoters: bax, bcl-Xs, caspase
● Inhibitors: bcl-2, bcl-XL
What are neutrophils?
● produced in bone marrow
● 50-70% of leukocyte population; phagocytic
○ Phagocytose cells and kill them intracellularly
● protect against acute infections
● contain primary (azurophilic) and secondary granules
● primary granules consist of myeloperoxidase enzyme, lysozyme, and ɑ-defensins
○ myeloperoxidase enzyme catalyzes the formation of hypochlorous acid and singlet oxygen (ROS)
■ responsible for pus and inflammations
○ lysozyme degrades peptidoglycan
● secondary granules consist of lactoferrin which sequestors iron and limits availability of iron to intracellular microbes -> growth inhibition of intracellular pathogens
● do not present antigens to T cells or initiate adaptive immunity
○ poorly express MHC on cell surface
○ only survive for one day
● Excessive neutrophil numbers indicate chronic infection
● Diapedesis: when neutrophils leave circulation and go to extravascular pools to mediate inflammation
What are eosinophils? How do they aid against parasitic infection?
● 1-3% of leukocyte population
● have bi-lobed nulcues
● contain basic granules in cytoplasm
● protect against parasitic infections
Can't ingest parasites - instead they rupture and release proteins that attack parasites
● contain basic proteins such as
○ major basic protein (MBP)
○ eosinophil cationic protein (ECP)
○ eosinophilic derived neurotoxin (EDN)
○ eosinophil peroxidase (EPO)
What are basophils? What immunoglobin is required to mediate allergic reactions?
● less than 1% of leukocyte population
● involved in Type I hypersensitivity reactions
cross-linking of IgE causes basophils to release pharmacologically active mediators (heparin and histamine) to mediate allergic reactions
○ upon degranulation, histamines released from basophils can cause contraction of smooth mm -> increased blood flow -> inflammation
● mast cells are differentiated basophils in tissue
What are monocytes? Do they express myeloperoxidase? Alpha defensins?
● first line of defense against pathogens
● 4-6% of leukocyte population, belong to myeloid lineage
● lack cytoplasmic granules
● kidney-shaped nucleus
● major phagocytic cells; more efficient than neutrophils
● go to various organs where they differentiate to macrophages
○ in lungs, alveolar macrophages
○ in liver, kupfer cells
○ in kidney, mesangial cells
○ in brain, microglial cells
● Monocytes and macrophages ingest micro-organisms and kill them intracellularly by different pathways
○ generation of reactive oxygen intermediates
○ reactive nitrogen intermediates, anti-microbial peptides
○ by fusion of phagosomes containing bacteria with lysosomes
○ antimicrobial peptides
○ *they express CD14 on cell surface
● monocytes do not have myeloperoxidase or ɑ-defensins*
● act as scavengers by clearing dead cells and debris
● Macrophages can present antigens in assoc. w/MHC molecules and initiate T-cell response
What are dendritic cells? How do they present extracellular protein antigens to CD4+ cells? How do they present viral proteins to CD8+ cells?
● most efficient antigen-presenting cells, capable of both phagocytosis and pinocytosis
● Processing of antigens by DCs for recognition by CD4 and CD8 T cell cells occurs in different compartments
● Usually an
extracellular protein antigen
is phagocytosed by DCs and is processed within
where the complex protein is broken down and is associated with
MHC class II
I* molecules and the entire complex is transported to the cell surface of DCs for CD4 recognition
, the secreted viral proteins from the intracellular virus
processed inside proteasomes of DCs
. The processed antigen is then transported to
by a transporter protein called
. Inside the rough endoplasmic reticulum the antigen associates with
MHC Class I
I* molecules and this processed antigen-MHC Class I molecules is transported to the cell surface of DCs for recognition by CD8+T cells
What are natural killer cells? What types of receptors do they express? What do they secrete?
● NK cells express killer activating receptors (KAR) and killer inhibitory receptors (KIR) on their cell surface
NK cells recognize abnormal cells that express low levels of MHC Class I molecules
● NK cells produce
n* that can kill the target cells
● Lymphocytes that do not express CD3, CD4 or CD8 (NKC)
What are lymphocytes?
● derived from lymphoblast progenitor cells (lymphoid lineage)
○ no changes in nuclear morphology
○ VERY specific receptors
○ all T cells have CD3 on cell surface
○ T cells classified as CD4 and CD8
■ CD4: helper T cells
■ CD8: cytotoxic T cells
What are Helper T cells? Which 2 cytokines are released by Th1? Which 3 cytokines are released by Th2?
● 25-35% of leukocyte population
● called helper T cells b/c produce cytokines such as IFN gamma that can enhance macrophage fxn to control intracellular pathogens
● T helper1 (Th1)
○ aid in cellular immunity
○ release cytokines such as IL-2 (T-cell growth factor) and IFN-gamma (activate innate immune system -> increase qty of anti-microbial peptides, etc.)
● T helper2 (Th2)
○ aid B cells to produce certain classes of antibodies
○ characterized by secretion of IL-4, IL-5 (produce certain classes of antibodies) and IL-10 (immunosuppressive)
What are cytotoxic T cells?
● form ⅓ of T cell population. Assoc w/ MHC I
● cytotoxic T-lymphocytes (CTLs) are able to kill target cells by directly inducing apoptosis
● pre-formed perforins are released at the target cell surface to generate transmembrane pore in target cell
● granulysins gain entry through these pores into the cytosol to induce apoptosis
● apoptotic signaling via membrane-bound molecules can occur via Fas on the target cell surface and Fas ligand on the CTL surface
What are B cells? What kind of antigens do they have? What is class switching?
● B lymphocytes develop in bone marrow
● Produce antibodies and express Bcell receptors (IgM) on surface
● Plasma cells: final descendent of B cells that produce antibodies
○ live for 30 days and do not express B cell receptor
○ Stellar or star-shaped nucleus
● B cells have 2 different antigens:
○ T cell independent (LPS)
○ and T cell dependent (protein)
○ B cells also have antigen receptors on cell surface: IgD
● Non-protein antigens such as LPS are not presented w/ MHC molecules (T cell independent)
○ binding of LPS and others alike to IgD directly activates B cells to produce IgM. Only IgM is produced
● Protein antigens: get internalized and processed and presented to T cells.
Class Switching: If protein antigen presented with MHC II, then recognized by CD4+T cells -> produces B-cell growth factor (IL-4) and B-cell stimulating factor (IL-5). These induce B-cells to produce antibodies that belong to any class - IgG, IgE and IgA (class switching)
Describe the thymus. What is its role in T cell development?
Thymus (undergoes involution)
● thymocytes become T lymphocytes
○ thymocytes do not yet have CD3, 4, or 8 receptors
● expression of specific receptors
● T cells learn to recognize self from non-self
● Once thymocytes get TCR and CD3, CD4, and CD8, they go through positive selection then negative selection (2 screenings)
○ positive selection promotes thymocytes with receptors that interact with self-MHC molecules and eliminates those that do not
○ The cells that pass the screening retain either CD4 or CD8, thus becoming single positive cells
■ cells lose one of two CD molecules
○ Single-positive T cells migrate to the medulla of the thymus where they encounter epithelial cells
○ negative selection eliminates thymocytes that react to self-antigens
T cells that survive both the screening alone leave the thymus
Describe the bone marrow. What is its role in T cell development?
● stem cells that are not ordained to migrate to thymus undergo development in bone marrow -> develop into B cells
● B cells acquire B cell receptor (BCR) on cell surface that is IgD**
● B cells that react to self-antigens are eliminated by apoptosis
● B cells that pass screening leave bone marrow and go to secondary lymphoid organs for further develop.
What are secondary lymphoid organs?
In the secondary lymphoid organs, T cells and B cells undergo further differentiation by cellular interactions and by exposure to antigens. This results in acquisition of additional markers on the cell surfaces of T cells and B cells that are critical in inducing the activation process
Describe the spleen. What is its role in T cell development?
● spleen is a filter for blood
● white pulp = lymphoid tissue
● red pulp = splenic cord and sinuses (RBCs) - (arterioles)
● lymphoid organ where T and B cells arrive
○ antigenic materials trapped and provided to these cells for recognition
○ T and B cells interact and exchange notes -> further development of acquisition markers
Describe the lymph nodes. What is its role in T cell development?
● mesh-like structures formed by DCs and macrophages
● filter antigens from lymph (made of cortex and medulla)
● superficial cortex (T-cell independent area) receives microbial antigens; B-cells in center of follicle proliferate in response to antigen (germinal center)
● T-lymphocytes are found in the deep cortex
● after further development, T and B cells exit lymph nodes via medulla
Describe the Payers Patches. What is its role in T cell development?
● present in submucosal region of alimentary canal
○ have cortex and medulla
● cells enter payers patches through cortex, leave via medulla
protect digestive system from intestinal flora
○ mucosa associated lymphoid tissue (MALT)
○ gut associated lymphoid tissue (GALT)
○ bronchus associated lymphoid tissue (BALT)
Describe innate immunity.
● It is pre-formed
● Does not have immunological memory
● Innate immunity does not improve over time
● Innate immunity is non-specific (can kill wide range of organisms)
Provide some examples of surface barriers in innate immunity.
● outermost layer of skin: stratum corneum, made of dead cells
○ cells are periodically sloughed off to prevent colonization of bacteria
● sebaceous glands secrete sebum and maintain low pH of 5.5 to prevent colonization of bacteria
● secretions of skin and eyes contain lysozyme to degrade peptidoglycan of gram-positive bacteria
● the vagina is colonized by lactobacillus that secretes in lactic acid (pH 4.5) to prevent microbe colonization
○ if lactobacillus is eliminated (tx w/antibiotics) -> increased risk for fungal infections!
● goblet cells secrete mucus to trap bacteria; cilia can then help with expulsion of this mucus
○ coordinated beating of ciliated epithelial cells in lungs helps drive this process of expulsion
● stomach cells have low pH; paneth cells also secrete ɑ-defensin (antimicrobial effects on pathogen)
What are pattern recognition receptors?
neutrophils, macrophages, and dendritic cells participate in innate defenses
phagocytic cells (all except NKC) recognize microbial infection using pattern recognition receptors such as:
● TLR-4 recognizes LPS of gram-negative bacteria
● TLR-2 recognizes peptidoglycan and lipotechoic acid of gram-positive bacteria
● complement receptors
○ once microbial infection is recognized, monocytes and neutrophils bind to microbes and engulf them
○ phagocytosis occur on cell surface areas called clatherin-coated pits
Describe the mechanism of phagocytosis.
● plasma membrane undergoes invagination
● loose ends of phagocytic membrane fuse together to form phagosome, endosome, or vacuole using clathrin
● once internalized, cell will use oxygen dependent or oxygen independent mechanisms to kill microbes
Describe oxygen-dependent killing mechanisms.
● NADPH reduces O2 to superoxide
● superoxide reacts with superoxide to form hydrogen peroxide, which can kill bacteria by forming hypochlorite via myeloperoxidase
● hypochlorite can further react with hydrogen peroxide to form singlet oxygen**
● neutrophils contain myeloperoxidase enzyme
● macrophages lack myeloperoxidase enzyme and hence cannot generate hypochlorite
○ can however generate superoxide and h2o2
○ can generate NO and reactive N-intermediates to control intra pathogens
Describe oxygen-independent killing mechanisms.
● phagosome containing bacteria fuses with lysosome
● lysosomes contain hydrolytic enzymes, lysozyme, lactoferrin, defensins, DNAse, and RNase
○ lysozyme present in macrophage and in primary granules can degrade peptidoglycan
○ lactoferrin in macrophages and in secondary granules sequesters iron and deprives pathogen
○ alpha defensins have antimicrobial effects
○ lipases and lysosomal enzymes damage by acting on cells DNA
Describe the interferon family.
● Interferons are a major cytokine - simply put - they send warning interferon to neighboring cells when attacked by virus - this interferon warning allows neighbor cells to prepare antiviral proteins to block virus
● family of related proteins each with slightly different physiological effects (2 classes)
● Type 1: released by human cells infected virus. Includes IFN-alpha and IFN - beta
● Type 2: IFN - gamma
● Lymphocytes secrete gamma (ɣ) interferon, but most other WBCs secrete alpha (ɑ) interferon
● Fibroblasts secrete beta (β) interferon
● Interferons also activate macrophages and mobilize NKs
● FDA-approved alpha IFN is used:
As an antiviral drug against hepatitis C virus
○ To treat genital warts caused by the herpes virus
● Genes that synthesize IFN are activated when a host cell is invaded by a virus
● Interferon molecules leave the infected cell and enter neighboring cells
● Interferon stimulates the neighboring cells to activate genes for Protein kinase R (PKR-an antiviral protein)
PKR nonspecifically blocks viral reproduction in the neighboring cell
What are natural killer cells?
● NK cells can lyse and kill cancer cells and virus infected cells
● Are a small, distinct group of large granular lymphocytes
● React nonspecifically and eliminate cancerous and virus-infected cells
Lyse target cells that have down-regulated expression of MHC Class I
● Express killer activation receptors (KAR) and killer inhibitory receptors (KIR - if MHC I engaged)
● Kill their target cells by releasing perforins and other cytolytic chemicals
Describe inflammation. What are the four cardinal signs of acute inflammation?
● The inflammatory response is triggered whenever body tissues are injured
● Prevents the spread of damaging agents to nearby tissues
● Disposes of cell debris and pathogens
● Sets the stage for repair processes
● The four cardinal signs of acute inflammation are
redness, heat, swelling, and pain
● infection and inflammation can lead to septic shock
What are the characteristics of septic shock? What is septic shock mediated by? What other cytokines are involved?
● disseminated intravascular coagulation
● all above events mediated by TNF-alpha
○ excess production of TNF-alpha in conjunction w/other cytokines such as IL-1 and IL-6 induce inflammation + septic shock
○ at optimal conc. TNF-alpha protects host by activating the immune syst
○ when in excess: causes muscular wasting (cachexia), anorexia, and inflammation
○ in conjunction w/IL-1 cause hyperpyrexia (elevationg in body temp)
What is the role of nitric oxide in sepsis? What is the role of TNF-alpha?
● TNF-alpha can activate eNOS (endothelium), nNOS (neurons), and iNOS (macrophages, smooth muscle)
○ this induces hypotension
TNF-alpha activates NO synthase in macrophages and endothelial cells -> vasorelaxation = hypotension
○ TNF-alpha also induces bradykinin synthesis which also inc NO production
● TNF-alpha also induces expression of tissue factor (TF) on mooncytes and neutrophils -> triggers clotting by extrinsic pathway
What is the alternate complement pathways?
● infection can release LPS, which directly activates C3
● C3 breaks into C3a (chemotactic) and C3b (MAC activator)
○ MAC induces osmotic disregulation of bacteria -> bacteria rupture
● C3b activates C5, which breaks into C5a and C5b
● C5a functions as an anaphylotoxin, inducing mast cells and basophils to release histamine
● histamines enhance vascular permeability
What is the role of chemokines in cell migration? What do neutrophils migrate in response to? What do monocytes and macrophages migrate in response to?
● Neutrophils migrate in response to
mnemonic: "Clean up on Aisle 8!"
● Monocytes and macrophages migrate in response to
(granulocyte macrophage colony stimulating factor), monocyte inflammatory protein (
) and regulated upon activation, normal T cell expressed and secreted (
TNF-a and expression of surface markers on endothelial cells (E-selectin, P-selectin and ICAM)
● enhanced expressions of P-selectin and E-selectin on endothelial cell surface facilitates binding of leukocytes
● enhanced expression of ICAM (intracellular adhesion molecules) cause increased binding of neutrophils/monocytes to endothelial cells
○ binding of monocytes to endothelial cells and increased vascular permeability result -> cells leave circulatory syst and go to site of infection -> this migration = diapedesis
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